Regulation of Cardiac Growth by Akt-FoxO Signaling

控制心肌细胞增殖和生长的分子机制是正常的基础 心脏发育和这些过程的失调导致先天性和成人心脏 疾病。在产前发育期间，心脏主要通过分化的增生性生长而生长。 随着发育的进行，肌节构筑明显增加。出生后， 心肌细胞退出细胞周期，心脏的生长很大程度上是由于心肌细胞肥大。 调控细胞增殖和肥大的不同调控机制 发育和控制围产期心肌细胞周期撤退尚不完全清楚。在……里面 FoxO转录因子被Akt磷酸化拮抗的骨骼肌和平滑肌直接调节 抑制细胞周期进程和促进肌肉萎缩的基因的表达。AKT的功能 发育中的心脏中的信号通路和FoxO转录因子将在胚胎中进行检测， 胎儿、新生儿和成年心肌细胞在细胞培养和遗传操作的小鼠模型中。这个 假说Akt介导的FoxO转录因子失活促进心肌细胞 在发育过程中促进细胞增殖和调节心脏生长。初步研究表明，FoxO是 在发育中的心脏中表达，胎儿心肌细胞经IGF-I处理后增加 通过依赖PI3K的机制促进细胞增殖和FoxO1的磷酸化。目标1.确定FoxO1是否 或FoxOS调节PI3K/AKT信号下游的增殖和成熟 或新生心肌细胞。目的2.确定FoxO1是否调节心肌细胞的差异生长和肥大 体内发育的心肌。目前的目标是确定FoxO转录因子是否受 AKT磷酸化控制心肌细胞增殖和细胞大小(肥大) 心肌细胞发育和成熟。长期目标是定义信号转导 发育中和成年心肌生长、分化和成熟的机制。 这些研究旨在揭示心脏发育的重要生长控制机制。 可用于治疗先天性或成人心脏病的肌肉。

The molecular mechanisms that control cardiomyocyte proliferation and growth are fundamental to normal heart development, and dysregulation of these processes contributes to congenital and adult cardiac disease. During prenatal development, the heart grows mainly through hyperplastic growth of differentiated cardiomyocytes, and increased sarcomeric architecture is apparent as development proceeds. Postnatally, cardiomyocytes withdraw from the cell cycle, and heart growth is due largely to cardiomyocyte hypertrophy. The regulatory mechanisms that control differential regulation of proliferation and hypertrophy during development and that control perinatal cardiomyocyte cell cycle withdrawal are not completely known. In skeletal and smooth muscle, FoxO transcription factors antagonized by Akt phosphorylation directly regulate expression of genes that inhibit cell cycle progression and promote muscle atrophy. The functions of the Akt signaling pathway and FoxO transcription factors in the developing heart will be examined in embryonic, fetal, neonatal and adult cardiomyocytes in cell culture and in genetically manipulated mouse models. The hypothesis is that Akt-mediated inactivation of FoxO transcription factors promotes cardiomyocyte proliferation and regulates heart growth during development. Preliminary studies demonstrate that FoxO are expressed in the developing heart, and treatment of fetal cardiomyocytes with IGF-I leads to increased proliferation and FoxO1 phosphorylation through a PI3K-dependent mechanism. Aim 1. Determine if FoxO1 or FoxOS regulate proliferation and maturation downstream PI3K/AKT signaling in cultured embryonic, fetal or neonatal cardiomyocytes. Aim 2. Determine if FoxO1 regulates differential growth and hypertrophy of the developing myocardium in vivo. The immediate goal is to determine if FoxO transcription factors regulated by Akt phosphorylation control cardiomyocyte proliferation and cell size (hypertrophy) at specific stages of cardiomyocyte development and maturation. The long term goal is to define signal transduction mechanisms underlying growth, differentiation and maturation of the developing and adult myocardium. These studies are designed to reveal developmentally important growth control mechanisms of cardiac muscle that could be exploited in the treatment of congenital or adult heart disease.